Results

Discussion

A number of trials have been conducted to determine the effectiveness of the new RSV prophylaxis preparations.7-10 The PREVENT study showed an overall 41% reduction in hospitalisation for RSV when RSV-IVIG was administered to 250 infants fitting the AAP criteria for treatment.9 However, RSV-IVIG has several disadvantages compared with the newer palivizumab preparation which make its widespread use in the UK unlikely. These include risk of fluid overload, requirement of intravenous cannulation and infusion over several hours, possibility of transmission of infection from IVIG donors, and disruption of the routine childhood vaccination schedule. The IMpact study was a multicentre international phase III trial undertaken to evaluate the safety and effectiveness of monthly administration of palivizumab as prophylaxis against serious RSV illness in high risk children.10 Children were eligible for recruitment if they were either 35 weeks gestation or less and 6 months of age or younger at the onset of the RSV season, or if they were 24 months or younger with a clinical diagnosis of CLD requiring ongoing medical treatment during the six months before the onset of the RSV season. The latter medical treatments comprised supplemental oxygen, steroids, bronchodilators, or diuretics, so the group was clearly heterogeneous with respect to severity of CLD. Palivizumab was administered to 1002 children and placebo to 500 children. Prophylaxis resulted in a 55% reduction in admission to hospital as a result of RSV infection, when the two recruitment groups were combined. However, the greatest reduction in admission rate (78%) occurred in children who were born at less than 35 weeks gestation but without CLD—that is, those at least risk of severe RSV illness. Children with CLD had a smaller reduction in admission rate (39%). Furthermore, the results of the study were expressed as relative risk reduction rather than absolute risk reduction, thereby exaggerating the treatment benefit.11 Neither the PREVENT nor the IMpact study showed a reduction in either days spent on PICU or requirement for mechanical ventilation for infants receiving prophylaxis, and neither study showed a reduction in mortality from RSV in these infants.

The incidence of hospitalisation for RSV among preterm infants reported in previous studies from North America varies between 2.8% and 37%.1 ,7-10 12-14The higher rates come either from studies looking only at preterm infants with underlying pulmonary or cardiac problems or from the control arms of randomised controlled trials for RSV-IG. These studies may not be representative of a typical neonatal unit preterm population. A population based study from northern California published recently reported a similar overall rate of hospitalisation to our study.14 The study also showed a higher rate of hospitalisation in infants who were oxygen dependent at 28 days of life, but was not able to report specific hospitalisation rates for infants with CLD on home oxygen or for infants with CLD who had come off supplementary oxygen in the six months before the RSV season (the first two categories of the AAP guidelines). Among 1721 infants with full follow up, there were no deaths from RSV, as in our study. The only previous UK study looking at hospitalisation for RSV included all infants, not only those born preterm, and found a national admission rate of 3%.15

Our study suggests that the first RSV season encountered accounts for most of the morbidity seen from RSV. This is in accordance with a study of 427 high risk infants by Wang et al which showed a significant decrease in frequency of RSV-LRTI and RSV hospitalisation with increasing age, with a major drop in those over 1 year.12

Considering the relatively low rates of hospitalisation for RSV found among preterm infants without recently treated chronic lung disease in the present and other studies, one must question the broadness of the AAP guidelines and the UK licensed indications detailed above in terms of the cost of RSV-IG prophylaxis. The cost information presented here is not intended to be a formal cost–benefit analysis which should take account of societal costs such as loss of parental working days and which is usually presented in terms of cost per life-year saved. Our study population is too small to perform a meaningful analysis of this type. Instead, we present a cost comparison from the perspective of a large regional neonatal unit. The potential cost of palivizumab prophylaxis for the infants less than 2 years of age with CLD on home oxygen was similar to the high cost of hospitalisation for the one infant admitted with RSV-LRTI in this group. For all other groups, the potential cost of palivizumab would have been far higher than the actual cost of hospitalisation for RSV. Our comparison is biased in favour of prophylaxis for the following reasons. Firstly, we have included infants admitted with RSV unknown LRTI in the hospitalisation costs; many of these infants were probably not suffering from RSV. Secondly, we have not included costs involved in palivizumab administration (for example, paediatric community nursing). Finally, we have not taken into account the fact that palivizumab will not prevent all admissions of cases with RSV.

Hall et al emphasise the importance of performing a local cost analysis before introducing RSV prophylaxis in a designated area.16 They acknowledge that most analyses will not include costs or benefits other than those directly encountered by the healthcare provider. They identify the important variables in such analyses as local rehospitalisation rate for RSV infection among ex-preterm infants (with and without CLD), and local average cost of a hospital admission for RSV for these groups of infants. They also suggest collecting these data for different gestational ages, as those infants who are relatively less preterm are likely to exhibit less morbidity from RSV. We have presented our data in categories corresponding to AAP guidelines rather than purely gestational age. This highlights the increased morbidity seen in the two groups with CLD compared with those without. In fact one of the two infants requiring ventilation for RSV was 29 weeks gestation at birth, not extremely preterm, but did have CLD.

Two cost effectiveness analyses for palivizumab use in the USA were published in 1999.17 ,18 Joffe et al have the advantage of using their population based RSV rehospitalisation data in their calculations.14 ,18 They present their cost effectiveness analysis for palivizumab firstly in terms of cost per RSV hospitalisation averted. This varies from $12 000 to $420 000 depending on gestational age, oxygen dependency at 28 days of life, and time of discharge from the NICU relative to the RSV season. They also present their analysis in terms of cost per life-year saved. However, as mentioned in the accompanying commentary,19 the authors make the assumption that because hospitalisation is reduced by 55% in the IMpact trial, it follows that mortality would be reduced by a similar rate. There is no evidence of a reduction in mortality from RSV in either the IMpact trial nor any other trial of RSV-IG and therefore in a cost–benefit analysis there are no life-years saved by prophylaxis.

In summary, no previous study has conclusively shown cost effectiveness for palivizumab. Our study suggests that treating infants with CLD on home oxygen would be relatively cost effective compared with other infants, although an incremental outlay may still be required. It seems likely that treating infants who are not on home oxygen would involve very large monetary outlay for little cost saving. Within the Thames regions, level 3 neonatal units are at present either not using palivizumab at all or restricting its use to selected very high risk infants. Based on the available research this would seem a sensible position to adopt. Even limiting palivizumab to all infants discharged on home oxygen, for the first RSV season encountered only, would cost in excess of £682 000 for infants in the Thames regions. Further prospective randomised controlled trials to investigate cost–benefit are unlikely. The rise and fall of ribavarin treatment for RSV infection reminds us that the paediatrician's need to “do something” based on limited trial evidence must be tempered with detailed postmarketing surveillance. Palivizumab is moderately effective but very expensive, and has been referred to the National Institute for Clinical Excellence (see footnote). Further prospective data on RSV readmission rates among ex-preterm infants with severe CLD are required, along with prospective audit data on the use, cost, and benefit of palivizumab in the UK.